Adamantane compounds

ABSTRACT

THE PRESENT INVENTION IS DIRECTED TO ADAMANTANE COMPOUNDS OF THE FORMULAE:   1-((R-OOC-)2-CH-)ADAMANTANE   1-(R&#39;&#39;-CO-C(-G)2-)ADAMANTANE   1-(HO-C(-R&#34;)2-C(-G)2-),2-(X)N-ADAMANTANE   1-(R&#34;-NH-CH(-R&#34;)-OOC-),2-(X)N-ADAMANTANE.(HN)N   1-(R&#34;-N(-X)-CH(-R&#34;)-C(-G)2-)ADAMANTANE.(HX)N   1,2-(-C(-G)2-C(-R&#34;&#39;&#39;)2-O-)ADAMANTANE   1,2-(-C(-G)2-CH(-R&#34;)-N(-R&#34;)-)ADAMANTANE.(HX)N   1-(G&#39;&#39;-O-C(-R&#34;&#39;&#39;)2-C(-G)2-),2-(G&#39;&#39;-O-)ADAMANTANE   WHEREIN EACH G INDEPENDENTLY REPRESENTS HYDROGEN OR STRAIGHT-CHAIN ALKYL OF FROM 1 TO 6, BOTH INCLUSIVE, CARBON ATOMS; G&#39;&#39; REPRESENTS HYDROGEN OR ACETYL; R REPRESENTS HYDROGEN OR ALKYL OF FROM 1 TO 6, BOTH INCLUSIVE, CARBON ATOMS; R&#39;&#39; REPRESENTS HALO, ALKOXY CONTAINING FROM 1 TO 6, BOTH INCLUSIVE, CARBON ATOMS IN THE ALKYL GROUP, HYDROGEN OR ALKYL OF FROM 1 TO 6, BOTH INCLUSIVE, CARBON ATOMS; EACH R&#34; INDEPENDENTLY REPRESENTS HYDROGEN OR ALKYL OF FROM 1 TO 6, BOTH INCLUSIVE, CARBON ATOMS; EACH R&#34;&#39;&#39; INDEPENTLY REPRESENTS HYDROGEN OR ALKYL OF FROM 1 TO 6, BOTH INCLUSIVE, CARBON ATOMS, OR BOTH R&#39;&#39; GROUPS TAKEN TOGETHER REPRESENT OXO(=O); X REPRESENTS HALO; AND EACH N INDEPENDENTLY REPRESENTS AN INTEGER OF FROM 0 TO 1, BOTH INCLUSIVE. THE TERMS &#34;HALO&#34; AND &#34;HALIDE&#34; ARE EMPLOYED HEREIN TO DESIGNATE OCCURRENCES OF BROMINE, CHLORINE, AND IODINE.

nitecl States Patent 01 hce ABSTRACT OF THE DISCLOSURE The presentinvention is directed to adamantane compounds of the formulae:

3,591 ,642 Patented July 6, 1971 wherein each G independently representshydrogen or straight-chain alkyl of from 1 to 6, both inclusive, carbonatoms; G represents hydrogen or acetyl; R represents hydrogen or alkylof from 1 to 6, both inclusive, carbon atoms; R' represents halo, alkoxycontaining from 1 to 6, both inclusive, carbon atoms in the alkyl group,hydrogen or alkyl of from 1 to 6, both inclusive, carbon atoms; each R"independently represents hydrogen or alkyl of from 1 to 6, bothinclusive, carbon atoms; each R' indepently represents hydrogen or alkylof from 1 to 6, both inclusive, carbon atoms, or both R' groups takentogether represent oXo(=-O); X represents halo; and each 11independently represents an integer of from 0 to 1, both inclusive. Theterms halo and halide are employed herein to designate occurrences ofbromine, chlorine, and iodine.

The adamantane compounds of Formulae VII and VIII are useful as agentsto achieve a depressant action on the central nervous system of warmblooded animals. The adamantane compounds of Formuae I, II, III, IV, Vand VI are useful as intermediates in the synthesis of the compounds ofFormuae VII and VIII.

BACKGROUND OF THE INVENTION Adamantane is a unique organic chemicalhaving the following structure:

As will be evident from this structural formula, the 1, 3, 5, and 7positions, the so-called bridgehead positions, are equivalent; andsimilarly, the 2, 4, 6, 8, 9 and 10 positions, the so-called methylenepositions, are equivalent. Although adamantane has been known for manyyears as a minor constituent of various petroleums, it was only around1960 that methods became available for its synthesis by ring closure ofthe bicyclo (3.3.1) nonane system. Since then, a considerable amount ofresearch has been carried out in an attempt to obtain variousderivatives of adamantane. While many derivatives have been procuredfrom adamantane, they are almost exclusively derivatives which arefunctionalized at the bridgehead positions or solely at the methylenepositions.

SUMMARY OF THE INVENTION The present invention provides a uniqueapproach to 1,2-disubstituted adamantane compounds.

The subject matter of the present invention can more readily beunderstood by reference to the following summary reaction scheme. Inthis presentation, the symbol Adis used to designate a l-adamantylradical, and the symbol Ad to designate a divalent 1,2-adamantyleneradical.

Part A alk alk

l Ad-C-COO alk ll Ad-C Gz-C-alk Ad-OGr-COOH Part B DETAILED DESCRIPTIONOF THE INVENTION Part A Part A of the present invention is concernedwith the synthesis of l-adamantaneethanol compounds serving as theimmediate precursors for the cyclization reactions of Part B.

In a first embodiment, compounds of Formula I;

I CH-00011) wherein R is as hereinabove defined, are prepared byreacting l-adamantanol with a dialkyl malonate, to obtain thecorresponding dialkyl l-adamantanemalonate (that compound of Formula Iwherein R represents alkyl), which is then hydrolyzed to obtain thecorresponding free acid (that compound of Formula I wherein R representshydrogen). The compounds of Formula I are useful as materials from whichto synthesize the compounds of Formulae II and III.

The above reaction of l-adamantanol and dialkyl malonate goes forwardreadily in the presence of a Lewis Acid catalyst, and at temperatures offrom -10 C. to 50 C., yielding the desired product and water asbyproduct. Preferably, the reaction is conducted in an inert liquidreaction medium, such as an alkane, for example, hexane. Particularlygood results are obtained when employing the reactants in substantiallyequimolecular amounts.

Following completion of the reaction, the desired dialkyll-adamantanemalonate can be separated from the reaction mixture as itsboron difluoride complex, in which case the complex is suspended in aninert hydrocarbon and distilled to drive off the boron complexingportion, leaving the free dialkyl ester which can be separated as suchor hydrolyzed with base to obtain the corresponding free acid. If thecomplex is not isolated, the reaction mixture is subjected to hydrolysisconditions wherefrom the malonic acid is obtained directly by methodswell known to the art.

The exact nature of complex obtained when boron trifluoride is employedin the reaction of an alkanol and a dialkyl malonate is not known.Generally, the following structure is assigned:

(I) alk f alkO BFZ and such structure is in conformity with theelemental analysis for such products, which analysis shows one mole ofBF per mole of malonate. However, an alternate resonating structure issometimes suggested:

Thus, it is believed that the following structure:

can be assigned to the boron complex obtained when boron trifluoride isemployed in the present reaction of l-adamantanol and a dialkylmalonate, although the alternate structure:

alkO

and

wherein the symbols G, R, R", X and n are as hereinabove defined, thefree acid of Formula I is decarboxylated to obtain l-adamantaneaceticacid, which can readily be converted to the corresponding acyl halide.To obtain those acyl halides wherein one or both G symbols stand foralkyl, the l-adamantaneacetic acid is esterified and then alkylated onthe alpha position, and the resulting alkylated ester converted to thecorresponding acyl halide by procedures which will be describedhereinafter. All acyl halides, regardless of whether G is hydrogen oralkyl, are then further reacted to obtain those products wherein Rrepresents hydrogen or alkyl, as defined.

The compounds of Formula II wherein R is halo, alkyl, or alkoxy areuseful as intermediates in the synthesis of the compounds of FormulaIII; and the compounds of Formula II wherein R is hydrogen or alkyl areuseful as intermediates in the synthesis of compounds of Formula IVwherein the n subscript of X (the substituent on the 2-position of theadamantane ring) is zero.

The above decarboxylation of the l-adamantanemalonic acid can be carriedout by heating it to a temperature above its thermal decompositiontemperature, such as a temperature in the range of 190 C. to 250 C. Thedecarboxylation goes forward readily merely upon heating to thespecified temperature range. Decarboxylation results in the desiredl-adamantaneacetic acid with carbon dioxide as a byproduct. Thel-adamantaneacetic acid product is cooled to effect crystallization andcan be purified by recrystallization from a suitable solvent.

Thereafter, l-adamantaneacetic acid is esterified, as by reaction withan excess amount of an alkanol in the presence of a mineral acid, forexample sulfuric acid. The resulting ester can be alkylated to introduceone or two groups of the identity of G onto the alpha carbon atom. Thealkylation comprises reacting the ester with an alkyl halide (GX) in thepresence of a compound which converts the ester to its enolate form, forexample, tritylsodium, sodium hydride, or sodium ethoxide. The reactionis carried out as described for method 299 of Wagner and Zook, SyntheticOrganic Chemistry (New York, N.Y.; Wiley and Sons, Inc., 1953), page 489and references therein cited. This method is taught as giving only pooryields of alkylated product where, as here, the alpha carbon atom hastwo hydrogen atoms; these low yields are purportedly due to the tendencyof such esters to undergo a competitive self-condensation reaction.However, the bulkiness of the adamantane ring severely limits suchself-condensation; thus, both alpha hydrogen atoms can be replaced bythis method, although yields on the second alkylation step will belower. Furthermore, two different alkyl groups can be introduced bystepwise reaction with each of two different alkyl halide compounds.

The l-adamantaneacetic acid esters thus obtained:

are readily hydrolyzed, by methods well known to the art, to the freeacid compounds:

('lGr-CO OH 0 corresponding alkyl esters, as by reaction with thealkanol The l-adamantaneacetyl halide compounds thus prepared arethereafter employed to prepare other compounds according to Formula IIwherein R' represents hydrogen or alkyl. Those products wherein Rrepresents hydrogen are readily prepared by the so-called Rosenmundreaction:

(NE -C catalyst, e.g., palladium [Wagner and Zook, op. cit., page 291,and Houben-Weyl, Methoden der Organischen Chemie (Stuttgart, Germany;George Thieme Verlag), 4th edition, Band 7, Teil 1, pages 289-290]. Thecorresponding ketones, e.g., those products of Formula II wherein Rrepresents alkyl of from 1 to 6, both inclusive, carbon atoms, areprepared by reacting the corresponding l-adamantaneacetaldehyde with analkyl magnesium halide:

O OH

[Wagner and Zook, op. cit, pages 159-160 and references therein citedand Kharasch et al., Grignard Reactions of Nonmetallic Substances (NewYork, NY; Prentice-Hall Inc., 1954), Chapter VI] and thereafteroxidizing (Wagner and Zook, op. cit., pages 323-326, and referencestherein cited) to obtain the desired ketone:

Thus, in these procedures are prepared all of the com pounds of theformula:

Ii oGz-o-R" wherein R" is hydrogen or alkyl as defined. However, many ofthese compounds are also readily prepared by an alternate reactionscheme. In this alternate scheme, a l-adamantaneacetyl halide is reactedwith diethyl malonate as its sodium or magnesiumethoxy derivative toyield an adamantaneacetyl malonate; this compound, in turn, ishydrolyzed and the diacid thus obtained decarboxylated to obtaincompounds wherein R" is an alkyl group in which the alpha carbon atombears at least one hydrogen. The reaction scheme can be summarized asfollows:

zHsOH Mg or Na laqueous acid I heat wherein R is hydrogen or C C alkyland G has the same meaning as hereinabove. The reaction is carried outin accordance with known procedures: see for example Walker et al.,Journal of the American Chemical Society 68 (1946),page 1386.

However, regardless of the manner in which the compound of the formula,

wherein G and R" have the same meaning as hereinabove, are useful asintermediates in the subsequent cyclization reactions of Part B to makethe products of Formulae V and VII, as well as the products of FormulaIV wherein the n subscript of X (at the 2 position of the adamantanering) is one, which latter products are similarly useful in thesubsequent cyclization reactions of Part B.

Subsequently, in a third embodiment, the l-adamantaneacetic acid, orcorresponding ester or acyl halide compounds, are reduced to prepare thecorresponding 1- adamantaneethanol compounds, those compounds of FormulaIII wherein each R represents hydrogen and n represents zero.

is reduced by reaction with lithium aluminum hydride in an inert liquidreaction medium. Suitable media include organic liquids, includingethers such as diethyl ether, tetrahydrofuran, and the dimethyl ether ofdiethylene glycol. The reaction mixture is preferably cooled below roomtemperature during initial contacting of the acid and lithiurn aluminumhydride. Thereafter, temperatures of C. to 60 C. are acceptable andconvenient. Particularly good results are obtained when employing thereactants in amounts representing three or more molecular proportions oflithium aluminum hydride for every two molecular proportions of thel-adamantaneacetic acid compound.

Those compounds of Formula III wherein one or both R" groups are otherthan hydrogen and wherein n is zero are also readily prepared. Whereonly one R is a group other than hydrogen, such compound is readilyachieved as hereinabove discussed, by reaction of the correspondingl-adamantaneacetaldehyde with an appropriate alkyl magnesium halide:

In either manner, there is achieved the desired compound of Formula IIIwherein one R" is a group other than hydrogen, and n is zero. Thosecompounds of Formula III wherein both R" groups are other than hydrogenand n is zero are prepared in a similar reaction of the compound ofFormula II wherein R is alkyl, as defined, with an alkyl magnesiumhalide:

II (I) G2 0 alkyl alkyl-MgX Thus, by these various procedures all thecompounds of Formula III wherein n is zero can be prepared. Thosecompounds according to Formula III wherein n is one are prepared andutilized as described hereinbelow in Part B.

Part B Part B of the present invention is concerned with the cyclizationof certain of the compounds prepared as described hereinabove in Part A,these reactions yielding additional new compounds of the followingformulae:

- (I-IX) n VI and VII As above defined, each G independently representshydrogen or straight-chain alkyl of from 1 to 6, both inclusive, carbonatoms; each R" independently represents hydrogen or alkyl of from 1 to6, both inclusive, carbon atoms; each R" independently representshydrogen or alkyl of from 1 to 6, both inclusive, carbon atoms, or bothR groups taken together represent 0x0; X represents halo; and each 11independently represents an integer of from 0 to 1, both inclusive. Thecompounds of Formula VI are useful as intermediates in the synthesis ofthe compounds of Formula VIII (Part C, hereinbelow), and the compoundsof Formula V are useful as intermediates in the synthesis of thecompounds of Formula VII. The utility of the compounds of Formulae VIIand VIII is discussed in more detail hereinbelow.

In the first synthetic procedure, suitable for the preparation of all ofthe compounds of both Formulae VI is initially reacted in an aqueousmedium with hypohalite, which can be supplied as the acid or as a salt,preferably with an alkaline earth or alkali metal. This reaction resultsin the preparation of the corresponding OX or --NX compound:

and

which rearrange to the corresponding 2-halo-1-adamantaneethanol or2-halo-l-adamantaneethylamine:

wherein G, R", and X have the same meaning as hereinabove.

In carrying out the first step of the above reaction scheme, the acycliccompound and the hypohalite are contacted, conveniently in an inertliquid reaction med um Suitable as such media are the halogenatedhydrocarbons, for example, carbon tetrachloride, dichloromethane,chloroform, and the like. The precise form in which the hypohalite issupplied to the reaction mixture is not critical; however, preferredforms are (1) a solution, freshly prepared, of a hypohalous acid such ashypochloric or hypoiodic and (2) an alkali metal hypohalite, forexample, sodium hypochlorite. The exact amounts of the reactants alsoemployed are not critical, some of the desired product being obtainedwhen employing any amounts. However, for good yields, it is necessarythat the hypohalite be supplied in excess, such as an amountrepresenting from 1 to 10 molecular proportions per molecular proportionof the starting l-adamanta-neethanol or l-adamantaneethylamine compound.The reaction goes forward over a wide range of temperatures, but isconveniently and preferably conducted at room temperature.

The reaction results in the preparation of the correspondingintermediate:

and

which in the instance of the latter type of compound, is readilyseparated from the reaction mixture by conventional procedures,typically by separation of the organic phase of the reaction mixture andremoval of the reaction medium from this phase by evaporation. In theinstance of the former type of product, many compounds cannot beseparated, inasmuch as they undergo spontaneous rearrangement to thecorresponding 2-halo-1- adamantaneethanol. This rearranged product, ofcourse, can likewise be separated from the reaction mixture byconventional procedures.

In the instance of those compounds which do not spontaneously undergorearrangement, as previously stated such rearrangement can be effectedby exposing the compound to ultraviolet light, conveniently by exposingthe original reaction mixture containing the compound to ultraviolet.The exact intensity of the ultraviolet is not critical, some of thedesired 2-halo-l-adamantaneethylamine being obtained even in thepresence of a weak source of ultraviolet. Separation and, if desired,purification of the 2-halo compound, are carried out in conventionalprocedures.

After the 2-halo-l-adamantaneethanol or 2-halo-1-adamantaneethylamine isobtained, cyclization thereof is readily elfected merely by heating at atemperature sufficiently high to drive off hydrogen halide, provisionbeing made for its safe removal. Generally, temperatures of 200 C. to280 C. give good results for the 2-halo-1- adamentaneethanol compounds,While with the 2-halo-1- adamantaneethylamines, temperatures of C. to250 C. generally give good results. Thus, in this manner are preparedall of the cyclic products of Formulae VI and VII.

13 In addition, cyclic products of Formula VI are readily prepared byanother cyclization procedure. In this procedure, l-adamantaneethanol isreacted with either lead tetraacetate or mercuric acetate; either agentcan be used alone or in conjunction with iodine, which enhances the rateof reaction.

wherein G and R" have the same meaning as hereinabove. When excess leadtetraacetate is employed, there is preferentially prepared thecorresponding compound of Formula VI wherein the both R'" groups takentogether represent oxo.

In carrying out the above reaction, the reactants are contacted in aninert liquid reaction medium, for example, a hydrocarbon such asbenzene; and the resulting reaction mixture is held for a period of timein the reaction temperature range, approximately C. to the boiling pointof the particular hydrocarbon solvent. Separation and purification ofthe cyclized product are carried out in conventional procedures.Ultraviolet light can be used to enhance the rate of reaction.

The amine products of Formulae 1V, V and VII are readily obtained aseither the free base or the corresponding hydrohalide salt. The salt isprepared by reacting the free base with a hydrogen halide; in manyinstances, it is preferred to separate the product as the hydrohalidesalt. When desired, the salt can be converted back to the free base byneutralization.

Part C As above defined, each G independently represents hydrogen orstraight-chain alkyl of from 1 to 6, both inclusive, carbon atoms; eachR independently represents hydrogen or alkyl of from 1 to 6, bothinclusive, carbon atoms or both R" groups taken together represent oxo;and G represents hydrogen or acetyl. The compounds of formulae VII andVIII are useful as agents to achieve a depressant action on the centralnervous system of warm blooded animals. The mode of administration isnot critical; oral administration or administration by parenteralinjection are suitable and preferred methods. Dosage rates vary with theparticular compound and the particular species of animal; but generally,significant depression is obtained with the compounds of Formula VIII atrates of 100 or more milligrams/kilogram of animal body weight, byintraperitoneal injection, and at rates of 400 or moremilligrams/kilogram of animal body weight, by oral administration. Withthe compounds of Formula VII, significant depression is obtained atdosage rates of 25 or more milligrams/kilogram of animal body weight.The compounds are thus useful to calm warm blooded animals for easierhandling. In use, the compounds are combined with standard inertpharmaceutical carriers to provide useful forms for administration,including tablets, capsules, solutions for injection, and the like.

In addition, the compounds of Formulae VII and VIII are useful asantibacterial, amoebocidal and antitrichomonal agents. Good in vitroactivity was found with aqueous formulations containing 500 microgramsor more per milliliter.

The derivatives of Formula VIII are obtainedby cleavage of startingmaterials of the formula:

wherein G and R'" have the same meaning as hereinabove. Several methodsof furan ring cleavage are known, and no precise method is critical tothe preparation of the compounds of Formula VIII. However, a convenientcleavage method for compounds where R' is hydrogen or alkyl is thereaction of the specified starting material with acetic anhydride inboron trifiuoride etherate. The reaction yields a diacetate; that is,product of Formula VIII wherein G is acetyl. The diacetate is hydrolyzedto obtain the corresponding diol; that is, product of Formula VIIIwherein G is hydroxy. The cleavage reaction goes forward at temperaturesover a wide range, but is most conveniently carried out at roomtemperature. Good results are obtained when employing the reactants inamounts representing an excess of the acetic anhydride, such as a 1- to20-fold excess, and a catalytic amount of the etherate.

The resulting diacetate can be separated, and if desired, purified byconventional procedures. Alternatively, the reaction mixture containingthe diacetate can be treated in situ with the hydrolysis agent toconvert the diacetate to the corresponding diol, which is similarlyseparated, and if desired, purified by conventional procedures.

A convenient method for the preparation of those products of FormulaVIII wherein the R groups are taken together and represent oxo involvesa simple alkaline hydrolysis of the corresponding cyclic product.

The 2-hyd1oxy-l-adamantaneethanol or 2-hydroxy-1- adamantaneacetic acidproduct obtained in accordance with Part C can also be converted back tothe corresponding cyclic product. Thus, in this embodiment, a compoundof the formula:

wherein G and -R"' have the same meaning as hereinabove, is treated, asdescribed hereinabove in Part B for the compounds of Formula III, withlead tetraacetate or with mercuric acetate in the presence of iodine; orby simply heating the compound. The resulting product is the samecyclized product obtained from the compounds of Formula III inaccordance with Part B:

Therefore, cleavage and cyclization can be carried out repeatedly, asdesired.

The following examples illustrate the present invention and will enablethose skilled in the art to practice the same.

EXAMPLE 1 l-adamantanemalonic acid 15.1 parts of l-adamantanol (0.11mole) and 17.6 parts of diethyl malonate (0.11 mole) were stirred inparts of n-hexane at 0-5 C. while gaseous boron trifiuoride was passedover the surface of the mixture. On saturation of the reaction mixturewith boorn trifiuoride, as indicated by fumes emitting from the dryingtube, boron trifiuoride passage was stopped but stirring was continuedat room temperature for 1.75 hours.

The mixture was then stirred in an ice-salt bath and sufficient 50percent aqueous potassium hydroxide was added to neutralize the excessacid, the whole being maintained below 10 C. throughout. Sixty parts ofethanol, parts of water, and 20 parts of potassium hydroxide were thenadded and the bulk of the hexane was removed by distillation through aVigreux column. The resulting mixture was refluxed for 20 hours. It wasthen allowed to cool to room temperature and extracted with ether. Theether extract was separated and washed with water. The resulting aqueousphase was stirred in an ice bath while 20 percent aqueous sulfuric acidwas slowly added until the pH was below 1. Initially a fine precipitatecontaining inorganic material was deposited. At low pH, a coarserprecipitate of the crude dicarboxylic acid precipitated and wascollected by filtration. Recrystallization of the latter precipitatefrom a hexane-acetone solvent mixture afforded 14 parts ofl-adamantanemalonic acid, M.P. 188- 192 C. (d).

Analysis.Calc. (percent): C, 65.52; H, 7.61. Found (percent): C, 65.80;H, 7.58.

EXAMPLE 2 Diethyl l-adamantanemalonate After a reaction between 15.1parts of I-adamantanol and 17.6 parts of diethyl malonate with borontrifluoride had been carried out as described hereinabove in Example 1,the mixture was cooled in an ice bath while 75 parts of 99 percentethanol were added with stirring. The temperature of the mixture wasmaintained below 5 C. while sufficient 5 percent aqueous potassiumhydroxide solution to make the mixture alkaline was added. The resultingmixture was rapidly extracted with ether. and the ether layer washedwith ice-cold water and dried over magnesium sulfate. The ether wasremoved by distillation to afford oily crystals of a boron difiuoridecomplex of diethyl l-adamantanemalonate. This complex was heated inboiling heptane, and the heptane was slowly distilled off through aVigreux column until the distillate was non-acidic. Diethyll-adamantanemalonate was ob tained from the residual oil by distillationunder reduced pressure to afford a colorless oil boiling in the range;128131 C./0.25 mm. Hg. Elemental analysis was carried out: found for C,69.54 (cal., 69.39); found for H, 8.99 (calc., 8.90).

EXAMPLE 3 l-adamantaneacetic acid 2.4 parts of l-adamantanemalonic acidwere heated; after liquefaction occurred, the substance was furtherheated to 185 C. for one hour. On cooling, there was obtained a whitecrystalline mass, which was recrystallized from aqueous acetone toproduce 1.3 parts of pure 1- adamantaneacetic acid, melting at about 100C. Elemental analysis was carried out: found for C, 74.01 (calc.,74.19); found for H, 9.39 (caL, 9.34).

EXAMPLE 4 l-adamantaneacetyl chloride Sixty parts of l-adamantaneaceticacid and 125 parts of thionyl chloride were heated together under refluxfor 2 'hours. Removal of the excess thionyl chloride by distillation atnormal pressure and distillation of the residue at reduced pressureafforded 61 parts of l-adamantaneacetyl chloride, distilling in therange 848 C./0.5 mm. Hg.

1 6 EXAMPLE 5 l-adamantaneethanol 2.5 parts of l-adamantaneacetic acidwere dissolved in 50 parts of anhydrous diethylene glycol dimethyl etherand 2 parts of lithium aluminum hydride were added carefully to thesolution with stirring and cooling. The resulting mixture was heated toC. with stirring for 8-12 hours, and after cooling, poured slowly ontocracked ice. Acidification, extraction into ether, separation andwashing of the organic phase with water, followed by removal of thesolvent by distillation afforded the desired 1- adamantaneethanol whichwas purified by crystallization to give 2 parts of pure product, meltingat about 73 74 C.

EXAMPLE 6 l-adamantaneethanol Twenty parts of l-adamantaneacetic acidwere added in portions to a cooled suspension of 8 parts of lithiumaluminum hydride in 400 parts of anhydrous diethylene glycol dimethylether. The reaction mixture was allowed to warm to room temperature, andthereafter stand overnight at room temperature. The excess lithiumaluminum hydride was destroyed by the cautious addition of ethanol, andthe resulting mixture poured onto cracked ice. Acidification, extractioninto ether, separation and washing the organic phase with water,followed by removal of the solvent afforded l-adamantaneethanol, whichwas purified by sublimation at reduced pressure to give 17.3 parts ofpure product, melting at about 76-78 C.

Analysis.Calc. for C H O' (percent): C, 79.94; H, 11.18. Found(percent): C, 79.67; H, 11.06.

EXAMPLE 7 2-chlor0-l-adarnantaneethanol CH2CH2OH Ten parts ofl-adamantaneethanol were dissolved in 100 parts of carbon tetrachlorideand the solution shaken vigorously during 10-15 minutes with threemilliliter portions of cold, freshly prepared, approximately 0.25 molarhypochlorous acid solution. After separation, the organic layer waswashed with 5 percent sodium bicarbonate solution, dried over anhydrouspotassium carbonate, and allowed to stand at room temperature overnight.Removal of the solvent afforded 11.0 parts of a pale yellow oilcontaining a number of components which were separated by chromatographyon silica gel to give 15.8 parts of crude 2-chloro-l-adamantaneethanol.

EXAMPLE 8 l-acetonyladamantane Diethyl ethoxymagnesium malonate wasprepared from diethyl malonate (68.6 g.), magnesium (10 g.), andanhydrous ethanol (51 ml.) in ether (51 ml.). The mixture was stirredand maintained at a gentle reflux while a solution containingl-adamantaneacetyl chloride (80 g.) in dry ether ml.) was slowly added.During the addition the reaction mixture became almost solid. When allthe ethereal acid chloride had been added, the mixture was allowed tostand for 2 hours, and was then treated with dilute sulfuric acid andether until the solid had all dissolved. The ether layer was separated,washed with water, and after removing the ether by distillation, theresidue was boiled under reflux for 16 hours with a mixture containingglacial acetic acid (220 ml.), sulfuric acid (30 ml.) and water (100ml.). After removing the bulk of the acetic acid by distillation invacuum, the cooled solution was neutralized with 20 percent sodiumhydroxide and extracted with ether. The ether extract was separated,washed with water and dryed over magnesium sulfate. The ether wasremoved by distillation to leave a colorless oil. Distillation of theoil at reduced pressure gave 1- acetonyladamantane, 57.4 g. (79 percentof theory), distilling at about 76-78 C./ 0.15 mm. Hg.

Analysis.--Calc. for C I-I (percent): C, 81.19; H, 10.49. Found(percent): C, 80.68; H, 10.76.

EXAMPLE 9 a,N-dimethyll-adamantaneethylamine CHz-OH-NHCHs Five parts ofl-acetonyladamantane, 97 parts of a percent solution of methylamine inethanol, and 10 parts of glacial acetic acid were boiled under refluxfor one hour. After cooling, 0.25 part of platinum oxide were added andthe mixture hydrogenated at 60 p.s.i. for four hours at room temperatureusing a Parr apparatus. The catalyst was removed by filtration, thefiltrate acidified with dilute acid, the ethanol removed therefrom bydistillation, and the resulting aqueous residue extracted with ether.The aqueous phase was basified and again extracted with ether. Removalof the ether and distillation of the residue afforded 4 parts of thedesired amine, Ot,N-dlmethyl 1- adamantaneethylamine, as a colorlessoil; B.P.=8284 C./0.55 mm. Hg.

Analysis.-Calc. for C H N (percent): C, 81.10; H, 12.15; N, 6.76. Found(percent): C, 80.66; H, 11.91; N, 7.12.

EXAMPLE 10 N-chloro-ot,N-dimethyll-adamantaneethylamine2-chloro-a,N-dimethyll-adamantaneethylamine hydrochloride 11.7 parts ofN-chloro-u,N-dimethyl-l-adamantaneethylamine dissolved in 400 parts of 5N sulfuric acid in glacial acetic acid. The solution was irradiated,using a 1 liter photochemical reactor, for 1.5 hours, after which time atest sample gave no reaction for N-chlorarnine when treated withpotassium iodide solution, thus showing that the reaction had proceededto completion. The mixture was basified with'20 percent sodium hydroxidesolution and extracted with ether. The ether extract was washed withwater, dried over anhydrous magnesium sulfate, and the ether removeduntil the residual volume equalled approximately m1. Dry hydrogenchloride was passed into the solution, thus forming the hydrochloridesalt of the amine which was recovered as a crystalline mass byfiltration and was recrystallized from ether/ethanol to give 10.9 partsof 2-chloro-a,N-dimethyl-l-adamantaneethylamine hydrochloride: M.P.=213C.

Analysis.Calc. for C H ClN-HCl (percent): C, 60.43; H, 9.05; N, 5.03.Found (percent): C, 60.25; H, 8.99; N, 4.95.

EXAMPLE 12 Adamantano(2,1-b)tetrahydrofuran l3HzCHz l-adamantaneethanol(0.9 g.; 0.005 mole) and lead tetraacetate (2.9 g.; 0.065 mole) inbenzene (35 ml.) were boiled under reflux, with stirring, for threehours. After cooling, the mixture was poured onto ice-water andextracted with ether. The ether layer was Washed with water, dried overmagnesium sulfate and the ether removed by distillation to leave an oil.Chromatography on silica gel (35 g.) in a 19:1 benzene-ethyl acetatesolvent mixture gave the pure cyclic ether, 0.78 g. Calculated for C H O(percent): C, 80.84; H, 10.18. Found (percent): C, 80.46; H, 9.89. Then.m.r. spectrum showed the presence of a doublet (l proton) at 6.657,confirming the cyclic nature of the product.

EXAMPLE 13 Adamantano (2,1-b) tetrahydrofuran A sample of2-chloro-l-adamantaneethanol, prepared as described in Example 7, washeated at 200 C. in an atrnosphere of nitrogen for 8 hours and theproduct chromato graphed on silica gel to giveadamantano(2,1-b)tetrahydrofuran.

EXAMPLE 14 Adamantano(2,1-b)tetrahydrofuran EXAMPLE 151,2-dimethyladamantano (2,1-b )pyrrolidine ([JH -CH-OH3 2 chloro-l-[Z(methylamino)propyl] adamantane obtained from 18.4 grams of thehydrochloride thereof prepared as described in Example 11 was heated inan atmos- 19 phere of nitrogen at 185-95" C. for 14 hours. Thereafter,the amine product was permitted to cool to room temperature, resultingin a somewhat gummy solid which was partitioned between ether and 2 Nhydrochloric acid. The aqueous phase was separated, made alkaline withpercent sodium hydroxide solution, and then extracted with ether. Theether layer was separated, washed with water, dried over magnesiumsulfate, and the ether removed by distillation leaving an oily residue.

The oil was dissolved in 100 milliliters of acetic anhydride, and theresulting solution was kept at room temperature overnight and thenrefluxed for 2 hours. The acetic anhydride was removed in an evaporator.The residue was again partitioned between ether and 2 N hydrochloricacid and the aqueous phase worked up as before to give a pale yellowoil, the desired 1,2-dimethyladamantano(2,1-b)adamantane.

EXAMPLE 16 1,2-dimethyladamantano(2,1-b)pyrrolidine hydrochloridel-adamantaneacetyl bromide Slightly over three molecular proportions ofl-adamantaneacetic acid are reacted with one molecular proportion ofphosphorus tribromide, to yield l-adamantaneacetyl bromide.

EXAMPLE 18 l-adamantaneacetyl iodide Dry hydrogen iodide is passed intoa solution of 1- adamantaneacety-l chloride, prepared as described inExample 4, to obtain the corresponding l-adamantaneacetyl iodide.

EXAMPLE 19 1-adamantanol and di-n-butyl malonate are reacted to yielddi-n-butyl l-adamantanemalonate (M.W., 350.5).

EXAMPLE 20 l-adamantanol and dimethyl malonate are reacted to yielddimethyl l-adamantanemalonate (M.W., 266.3).

EXAMPLE 21 l-adamantanol and diisopropyl malonate are reacted to yielddiisopropyl l-adamantanemalonate (M.W., 322.4).

EXAMPLE 22 l-adamantaneacetic acid and excess methanol are reactedtogether, in the presence of a minor amount of sulfuric acid, yieldingmethyl 1 adamantaneacetate (M.W., 208.3).

EXAMPLE 23 l-adamantaneacetic acid and excess isobutanol are reactedtogether in the presence of a minor amount of sulfuric acid, yieldingisobutyl l-adamantaneacetate (M.W., 250.4).

EXAMPLE 24 l-adamantaneacetyl chloride and gaseous hydrogen are reactedtogether in xylene, in the presence of a minor amount of palladium onbarium sulfate, to yield 1-adamantaneacetaldehyde (M.W., 178.3).

20 EXAMPLE 2s l-adamantaneacetaldehyde and ammonia are reacted together,under the hydrogenation conditions of Example 24, yieldingl-adamantaneethylamine (M.W., 179.3).

EXAMPLES 2627 l-adamantaneethylamine and sodium hypochlorite are reactedtogether, yielding 2-chloro 1 adamantaneethylamine (M.W., 213.8) andupon heating, adamantano (2, 1-b)pyrrolidine (M.W., 177.3).

EMMPLES 28-30 l-acetonyladamantane, prepared as described in Example 8,and sec-butylamine are reacted together, yieldingN-sec-butyl-a-methyl-l-adamantaneethylamine. Upon reaction with sodiumhypoiodite, there is obtained 2-iodo- N-sec-butyl-a-methyl 1adamantaneethylamine (M.W., 375.3). Cyclization produces 1 sec butyl 2methyladamantano(2,1-b)pyrrolidine:

(FI CH-CH3 N-seo-buty1 EXAMPLES 31-34 1 adamantaneacetaldehyde and npropylmagnesium bromide are reacted together, and the resulting productoxidized to yield 1-(butyrylmethyl)adamantane (M.W., 220.4), which isconverted by reductive amination with methylamine to a-n-propyl-N-methyl1 adamantane ethylamine (M.W., 235.4). This latter product is reactedwith hypochlorous acid, yielding the corresponding 2-chloro-a-n-propyl-N-methyl 1 adamantaneethylamine, which upon heatingcyclizes to 1-methyl-2-n-propyladamantano(2,1-b)pyrrolidine:

EXAMPLE 35 Diacetate of 2-hydroxy-1-adamantaneethanol A mixture ofadamantano(2,1-b)tetrahydrofuran 11.3 g.), acetic anhydride ml.) andboron trifluoride etherate (12.5 ml.) were mixed and permitted to standat room temperature for two hours and then poured onto cracked ice (250g.) and allowed to stand overnight. As a result of these operations,there was obtained, in solution, the diacetate of2-hydroxy-l-adamantaneethanol.

EXAMPLE 36 Z-hydroxyl-adamantaneethanol The solution prepared asdescribed in Example 35 and containing the diacetate of 2-hydroxy-1-adamantaneethanol was neutralized with 20 percent sodium hydroxide andextracted with ether. The organic phase was washed with water, driedover magnesium sulfate, and the ether removed by distillation to afiord2-hydroxy-1-adamantaneethanol as the diacetate, as an oil which was notfurther purified. The oil was taken up in ethanol (100 ml.). Potassiumhydroxide (12 g.) was added, and the mixture boiled under reflux forthree hours. Water (250 ml.) was added and the ethanol removed bydistillation to give the Z-hydroxy-l-adamantaneethanol as a crystallinedeposit which was recovered by filtration and dried to give 9.32 g. ofproduct. Recrystallization from acetone/ hexane afforded pure2-hydroxy-l-adamantaneethanol, 8.02 g., M.P., 98-100 C.

Alzalysis.Calc. for C H O (percent): C, 73.43; H, 10.27. Found(percent): C, 73.70; H, 10.33.

EXAMPLE 37 Adamantano (2,1-b tetrahydrofuran-Z-one One part of2-hydroxy-l-adamantaneethanol, 46 parts of lead tetraacetate and 50parts of benzene were boiled under reflux for three hours. The mixturewas allowed to cool and then poured into water. Ether was added and theorganic phase was separated, washed with water, aqueous 5 percent sodiumbicarbonate solution, again with water, and then dried over magnesiumsulfate. The ether was re moved by distillation leaving an almostcolorless oil containing several components. Chromatography of the oilon silica-gel yielded a fraction containing 0.35 part of an oil whichshowed absorption in the infrared at 1780 cur-' indicating the desiredadamantano(2,1-b)tetrahydrofuran- 2-one product.

EXAMPLE 38 2-hydroxy-l-adamantaneacetic acid Alkaline hydrolysis of theadamantano(2,1-b)tetrahydrofuran-Z-ofie of Example 37, and subsequentwork up, yielded 2-hydroxy-l-adamantaneacetic acid. It wasrecrystallized from ethylacetate-n-hexane. The recrystallized substancemelted at about 112.5-114 C.

EXAMPLE 39 Adamantano(2,1-b)tetrahydrofuran-Z-one Sublimation of2-hydroxyl-l-adamantaneacetic acid in vacuo yieldedadamantano(2,l-b)tetrahydrofuran-Z-one as a waxy solid melting at about81-84 C.

EXAMPLES 40-81 The following additional examples are prepared inaccordance with the foregoing examples and teachings:

Name: Molecular weight Diacetate of B-n-butyl-B-ethyl-Z-hydroxy-1-adamantaneethanol 364.5 fl-n-Butyl-B-ethy1-2-hydroxy 1 adamantaneethanol280.5 Diacetate of u,B dimethyl 2 hydroxy-1- adamantaneethanol 308.4 a dDirnethyl 2 hydroxy-l-adamantaneethanol 224.3 Diacetate ofa,oc-di-11-h6Xyl 2 hydroxy-1- adamantaneethanol 448.7 a,a-Di-n-hexyl 2hydroxy 1 adamantaneethanol 364.6 Diacetate of Ot,06 dimethyl 2hydroxy-1- adamantaneacetic acid 322.4 a,a-Dimethyl 2hydroxy-l-adamantaneacetic acid 238.3 a,ot-Dirnethyl-l-adamantaneacetylbromide 285.2 Methyl ot-n-hexyl-l-adamantaneacetate s 282.4a-n-Butyl-a-methyl 1 adamantaneacetaldehyde 248.4l-(n-Heptanoylmethyl)adamantane 262.4 a,ot,6,;8-Tetramethyl-l-adamantaneethanol 236.4 ot,ot,B,,8-Tetramethyl 2chloro 1 adamantaneethanol 270.8 2,2,3,3Tetrarnethyladainantano(2,1-b)-tetrahydrofuran 234.4

,B-Ethyl-a-n-hexyl 1 adamantaneethanol 292.5 fi-Ethyl-u-n-hexyl 2 iodo 1adamantaneethanol 418.4 3-Ethyl 2 n hexylamantano(2,1-b)tetrahydrofuran290.5 [3,;3-Dimethyl-N-chloro 1 adamantaneethylamine 241.85,,8-Dimethyl-2-chloro 1 admantaneethylamine 241.8

a,N-Dimethyl-p-n-hexy1 1 adamantanethyl- 22 amine 277.5a,N-Dimethyl-fi-n-hexyl N bromo 1 adamantaneethylamine 370.4 3-n-Butyl 2ethyl 1 methyladamantano- (2,l-b)pyrrolidine 261.5 3 nPropyladamantano(2,1-b)tetrahydrofuran 220.4 2-t-butyl 1methyladamantano(2,1-b)pyrrolidine 247.4 Di-n-hexyl-l-adamantanemalonate407.6 a-n-Hexyl-l-adamantaneacetyl chloride 296.9 2-chloro fl n butyl ,8ethyl-l-adamantaneethanol 288.8

a,m-Di-n-hexyl-l-adamantaneethanol 348.6 2-iodo-a,;3 di n propyl ladamantaneethanol 390.4 3-n-butyl 3ethyladamantano(2,1-b)tetrahydrofuran 262.4 2,2 di nhexyladamantano(2,1-b)tetrahydrofuran 346.6 2,3 di npropyladamantano(2,1-b)tetrahydrofuran 262.4 N,oz,fl,fl tetramethyl 1adamantaneethylamine 235.4 2-chloro ,6 ethyl B npropyl-N-n-hexyll-adamantaneethylamine 368.1 fi-Methyl N n butyl N iodo1 adamantaneethylamine 375.3 1,2,3,3tetramethyladamantano(2,1-'b)pyrolidine 233.4 and its hydrochloride269.9 1 n butyl 2 methyladamantano(2,1-b)

pyrrolidine 247.4 and its hydrobromide 328.4 3- ethyl 3 npropyl-l-n-hexyladamantano- (2,1-b)pyrrolidine 331.6 and its hydriodide459.5

In preferred embodiments, the present invention is directed to subgeneraas follows:

CH -CHMN I All! (HX) u VIa mg-011M" VIIa (lJH -GHM VIII-a wherein Mrepresents hydrogen or loweralkyl of from 1 to 3, both inclusive, carbonatoms, the same moiety in each occurrence; M represents chloro,hydrogen, loweralkyl of from 1 to 3, both inclusive, carbon atoms, orloweralkoxy of from 1 to 3, both inclusive, carbon atoms; each Mindependently represents hydrogen or loweralkyl of from 1 to 3, bothinclusive, carbon atoms; M represents hydrogen or acetyl, the samemoiety in each occurrence; X represents bromo, chloro, or iodo; and each11 independently represents an integer of from to 1, both inclusive.

The compounds of these preferred embodiments exhibit to an enhanceddegree the properties generally exhibited by the present invention. Inaddition, they admit of ready synthesis, in accordance with the methodsdescribed hereinabove.

We claim:

1. The compound of the formula wherein each G independently representshydrogen or straight-chain alkyl of from 1 to 6, both inclusive, carbonatoms; G represents hydrogen or acetyl; and each R independentlyrepresents hydrogen or alkyl of from 1 to 6, both inclusive, carbonatoms, or both R groups taken together represent oxo(=0).

2. The compound of the formula References Cited UNITED STATES PATENTS8/1966 Klootwuk 26078.3 12/1967 Schneider 260-617F OTHER REFERENCESStetter et al., Ber. 93, (1960), pp. 2054-2057, Q0104.

Smith et al., J. Org. Chem, 26 (1961), pp. 2027- 2212, Q0241J6.

Hock et al., Record, 85, (1966), pp. 1054-1060, Q01R3.

Fort et al., Chem. Rev. 64, (1964), pp. 277, 288, 290, 296-299, Q01A56J.

BERNARD HELFIN, Primary Examiner J. E. EVANS, Assistant Examiner US. Cl.X.R.

